bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2023‒10‒29
six papers selected by
Kyle McCommis, Saint Louis University
  1. Dual roles of myocardial mitochondrial AKT on diabetic cardiomyopathy and whole body metabolism.
  2. Depressed Proximal Glycolysis in Myocardium Of Human Heart Failure with Preserved Ejection Fraction.
  3. Impact of SGLT2 inhibitors on patient outcomes: a network meta-analysis.
  4. mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy.
  5. CD36 as a gatekeeper of myocardial lipid metabolism and therapeutic target for metabolic disease.
  6. Metabolome Profiling in the Plasma of Dogs with Idiopathic Dilated Cardiomyopathy: A Multiplatform Mass-Spectrometry-Based Approach.
  1. Cardiovasc Diabetol. 2023 Oct 27. 22(1): 294
    Dual roles of myocardial mitochondrial AKT on diabetic cardiomyopathy and whole body metabolism.
    Yu-Han Chen, Albert P Ta, Yumay Chen, Hsiao-Chen Lee, Wenjun Fan, Phang-Lang Chen, Maria C Jordan, Kenneth P Roos, Grant R MacGregor, Qin Yang, Robert A Edwards, Junfeng Li, Ping H Wang.
      BACKGROUND: The PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to mitochondria in the myocardium. Mouse models of diabetes exhibit impaired mitochondrial AKT signaling but the implications of this on cardiac structure and function is unknown. We hypothesized that loss of mitochondrial AKT signaling is a critical step in cardiomyopathy and reduces cardiac oxidative phosphorylation.METHODS: To focus our investigation on the pathophysiological consequences of this mitochondrial signaling pathway, we generated transgenic mouse models of cardiac-specific, mitochondria-targeting, dominant negative AKT1 (CAMDAKT) and constitutively active AKT1 expression (CAMCAKT). Myocardial structure and function were examined using echocardiography, histology, and biochemical assays. We further investigated the underlying effects of mitochondrial AKT1 on mitochondrial structure and function, its interaction with ATP synthase, and explored in vivo metabolism beyond the heart.
    RESULTS: Upon induction of dominant negative mitochondrial AKT1, CAMDAKT mice developed cardiac fibrosis accompanied by left ventricular hypertrophy and dysfunction. Cardiac mitochondrial oxidative phosphorylation efficiency and ATP content were reduced, mitochondrial cristae structure was lost, and ATP synthase structure was compromised. Conversely, CAMCAKT mice were protected against development of diabetic cardiomyopathy when challenged with a high calorie diet. Activation of mitochondrial AKT1 protected cardiac function and increased fatty acid uptake in myocardium. In addition, total energy expenditure was increased in CAMCAKT mice, accompanied by reduced adiposity and reduced development of fatty liver.
    CONCLUSION: CAMDAKT mice modeled the effects of impaired mitochondrial signaling which occurs in the diabetic myocardium. Disruption of this pathway is a key step in the development of cardiomyopathy. Activation of mitochondrial AKT1 in CAMCAKT had a protective role against diabetic cardiomyopathy as well as improved metabolism beyond the heart.
    Keywords:  ATP synthase; Diabetic cardiomyopathy; Fatty liver; Heart failure; Mitochondria dysfunction; Mitochondrial AKT; Obesity
    DOI:  https://doi.org/10.1186/s12933-023-02020-1
  2. medRxiv. 2023 Oct 02. pii: 2023.09.30.23296261. [Epub ahead of print]
    Depressed Proximal Glycolysis in Myocardium Of Human Heart Failure with Preserved Ejection Fraction.
    Navid Koleini, Mariam Meddeb, Mohammad Keykhaei, Seoyoung Kwon, Liang Zhao, Virginia Hahn, Kavita Sharma, Erika L Pearce, David A Kass.
      Heart failure with preserved ejection fraction (HFpEF) accounts for >50% of all heart failure world-wide and remains a major unmet medical need. The most effective recently approved treatments were first developed for diabetes, suggesting metabolic defects are paramount. Myocardial metabolomics in human HFpEF has identified reduced fatty acid and branched chain amino acid catabolism, but the status of glycolysis is unknown. Here we performed targeted metabolomics and protein analysis of glycolytic pathway enzymes in myocardial biopsies of patients with HFpEF versus HF with reduced ejection fraction (HFrEF0 or non-failing controls. Glucose was increased in HFpEF myocardium, but immediate downstream glycolytic metabolites (glucose-6 phosphate, fructose 1,6 diphosphate), were more reduced in HFpEF than the other groups, as were their associated synthetic enzymes hexokinase and phosphofructokinase. Pyruvate was also reduced in HFpEF versus controls. These changes were either not present or substantially less so in HFrEF. Suppression of proximal glycolysis was also coupled to lower metabolites and proteins in the pentose phosphate pathway but was independent of diabetes or obesity. These findings support marked metabolic inflexibility in HFpEF and identifies very proximal blockade in glucose metabolism. Efforts to improve metabolic use of carbohydrates in HFpEF will likely need to target these proximal glycolytic enzymes.
    DOI:  https://doi.org/10.1101/2023.09.30.23296261
  3. Cardiovasc Diabetol. 2023 Oct 27. 22(1): 290
    Impact of SGLT2 inhibitors on patient outcomes: a network meta-analysis.
    Jui-Yi Chen, Heng-Chih Pan, Chih-Chung Shiao, Min-Hsiang Chuang, Chun Yin See, Tzu-Hsuan Yeh, Yafei Yang, Wen-Kai Chu, Vin-Cent Wu.
      BACKGROUND: A comprehensive network meta-analysis comparing the effects of individual sodium-glucose cotransporter 2 (SGLT2) inhibitors on patients with and without comorbidities including diabetes mellitus (DM), heart failure (HF), and chronic kidney disease (CKD) has not been previously conducted.METHODS: We searched PubMed, Embase, Cochrane, and ClinicalTrials.gov for randomized controlled trials up to March 28, 2023. Network meta-analysis using a random-effects model was conducted to calculate risk ratios (RRs). Risk of Bias tool 2.0 was used to assess bias, and CINeMA to assess the certainty of evidence. In the subgroup analysis, the SGLT2 inhibitors were classified into highly (dapagliflozin, empagliflozin, and ertugliflozin) and less selective SGLT2 inhibitors (canagliflozin and sotagliflozin).
    RESULTS: A total of fourteen trials with 75,334 patients were analyzed. Among these, 40,956 had taken SGLT2 inhibitors and 34,378 had not. One of the main results with particular findings was empagliflozin users had a significantly lower risk of all-cause death compared to dapagliflozin users in DM population (RR: 0.81, 95% CI 0.69-0.96). In HF population, sotagliflozin users had a borderline significantly lower risk of CV death or hospitalization for HF (HHF) than dapagliflozin users (RR: 0.90, 95% CI 0.80-1.01). In non-HF population, those who used canagliflozin had a significantly lower risk of CV death or HHF compared with those who used dapagliflozin (RR: 0.75, 95% CI 0.58-0.98). At last, for HF patients, those who used less selective SGLT2 inhibitors had a significantly lower risk of MACEs compared to those who used highly selective SGLT2 inhibitors (RR: 0.75, 95% CI 0.62-0.90).
    CONCLUSIONS: Our network meta-analysis revealed that empagliflozin users with diabetes experienced a lower risk of dying from any cause than those using dapagliflozin. Additionally, canagliflozin users demonstrated a reduced risk of cardiovascular death or HHF compared to dapagliflozin users in those without HF. In HF patients, less selective SGLT2 inhibitors showed superior CV composite outcomes, even surpassing the performance of highly selective SGLT2 inhibitors.
    TRIAL REGISTRATION: PROSPERO [CRD42022361906].
    Keywords:  Chronic kidney disease; Diabetes; Heart failure; Network meta-analysis; SGLT2 inhibitor
    DOI:  https://doi.org/10.1186/s12933-023-02035-8
  4. Int J Mol Sci. 2023 Oct 11. pii: 15078. [Epub ahead of print]24(20):
    mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy.
    Sumit Saha, Xianjun Fang, Christopher D Green, Anindita Das.
      Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium-glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.
    Keywords:  AMPK; SGLT2i; diabetes; diabetic cardiomyopathy; mTORC1/2
    DOI:  https://doi.org/10.3390/ijms242015078
  5. Physiol Rev. 2023 Oct 26.
    CD36 as a gatekeeper of myocardial lipid metabolism and therapeutic target for metabolic disease.
    Jan F C Glatz, Lisa C Heather, Joost J F P Luiken.
      The multifunctional membrane glycoprotein CD36 is expressed in different types of cells and plays a key regulatory role in cellular lipid metabolism. CD36 facilitates the cellular uptake of long-chain fatty acids, mediates lipid signaling, and regulates storage and oxidation of lipids in various tissues with active lipid metabolism. CD36 deficiency leads to marked impairments in peripheral lipid metabolism, which consequently impacts on the cellular utilization of multiple different fuels, due to the integrated nature of metabolism. The functional presence of CD36 at the plasma membrane is regulated by its reversible subcellular recycling from and to endosomes, and is under the control of mechanical, hormonal and nutritional factors. Aberrations in this dynamic role of CD36 are causally associated with various metabolic diseases, in particular insulin resistance, diabetic cardiomyopathy, and cardiac hypertrophy. Recent research in cardiac muscle has disclosed the endosomal proton pump v-ATPase as a key enzyme regulating subcellular CD36 recycling and being the site of interaction between various substrates to determine cellular substrate preference. In addition, evidence is accumulating that interventions targeting CD36 directly or modulating its subcellular recycling are effective for the treatment of metabolic diseases. In conclusion, subcellular CD36 localization is the major adaptive regulator of cellular uptake and metabolism of long-chain fatty acids, and appears a suitable target for metabolic modulation therapy to mend failing hearts.
    Keywords:  CD36; SR-B2; fatty acid uptake; lipid metabolism; metabolic disease
    DOI:  https://doi.org/10.1152/physrev.00011.2023
  6. Int J Mol Sci. 2023 Oct 14. pii: 15182. [Epub ahead of print]24(20):
    Metabolome Profiling in the Plasma of Dogs with Idiopathic Dilated Cardiomyopathy: A Multiplatform Mass-Spectrometry-Based Approach.
    Ivana Rubić, Stefan Weidt, Richard Burchmore, Alan Kovačević, Josipa Kuleš, Peter David Eckersall, Marin Torti, Ines Jović, Mislav Kovačić, Jelena Gotić, Renata Barić Rafaj, Predrag Novak, Marko Samardžija, Vladimir Mrljak.
      Dilated cardiomyopathy is one of the important diseases in dogs and humans. The second most common cause of heart failure in dogs is idiopathic dilated cardiomyopathy (iDCM), which results in heart failure or sudden cardiac death due to arrhythmia. This study aimed to determine changes in the plasma metabolome of dogs with iDCM compared to healthy dogs. For that purpose, a multiplatform mass-spectrometry-based approach was used. In this study, we included two groups of dogs: 12 dogs with iDCM and 8 healthy dogs. A total of 272 metabolites were detected in the plasma samples of dogs by combining three approaches but four MS-based platforms (GC-MS, LC-MS (untargeted), LC-MS (targeted), and FIA-MS (targeted) methods). Our findings demonstrated changes in the canine plasma metabolome involved in the development of iDCM, including the different concentrations of amino acids, biogenic amines, acylcarnitines, triglycerides and diglycerides, sphingomyelins, and organic acids. The results of this study will enable the detection and monitoring of pathophysiological mechanisms involved in the development of iDCM in the future.
    Keywords:  chromatography; dogs; idiopathic dilated cardiomyopathy (iDCM); mass spectrometry; metabolomics; plasma samples
    DOI:  https://doi.org/10.3390/ijms242015182
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